Patients diagnosed with glioblastoma (GBM) generally have about a year to live. There is no cure for this malignant type of brain cancer. The disease generally manifests with subtle changes in brain function, and becomes worse with seizures, loss of sensation or equilibrium, and progresses to loss of motor function and mental ability, to finally, death. Surgery, focused radiation, and medical treatment may slow the disease down and delay death by several months, but unfortunately, this often comes at the expense of normal function as neurons, glia, and axonal pathways are damaged by the treatment) Wrensch, et al., Neuro-oncol., 4:278-299 (2002)).
Surgery is often done primarily to debulk the tumor, thereby temporarily restoring function to surrounding brain regions that were compressed by tumor expansion. A successful tumor resection may remove billions of tumor cells. But inevitably, due to its infiltrative nature, tens of millions of tumor cells remain within the brain after surgery (Croteau, et al., Cancer Research, 67(6), 2840-2848 (2007)). A critical feature of GBMs is that tumor cells are invasive, migrating away from the main tumor body, and continuing to divide elsewhere in the brain. This is one reason why approaches to treatment that focus on a tumor mass are ultimately not successful at eliminating the disease.
A considerable number of viruses have been tested for potential oncolytic activity against glioblastoma (Parker, et al., Neurotherapeutics, 6:558-569 (2009)). These include human pathogenic viruses that were genetically attenuated to render them safe enough for human application, for example HSV (Todo T, Front Biosci., 13:2060-2064 (2008)) and adenovirus (Nandi, et al., Expert Opin. Biol. Ther., 9:737-747 (2009); Chiocca, et al., Mol. Ther., 16:618-626 (2008)), and viruses based on vaccination strains, including polio (Dobrikova, et al., Mol. Ther., 16:1865-1872 (2008)), measles (Phuong, et al., Cancer Res, 63:2462-2469 (2003)), and vaccinia (Lun, et al., Mol. Ther., 18:1927-1936 (2010)), or adeno-associated viral vectors expressing various genes (Maguire, et al., Mol. Ther., 16:1695-1702 (2008)). However, HSV and retroviruses can either enter a latent mode and re-emerge later, or can integrate into host chromosomes, enhancing an oncogenic potential. Furthermore, many of these viruses share the potential problem that most humans have been exposed to these viruses before and their efficacy after systemic application may be challenged by pre-existing immunity.
A promising alternative is the use of viruses that are non-human pathogens but that display a tropism for tumors, as is the case with myxoma (Lun, et al., Cancer Res, 65:9982-9990 (2005)), Newcastle disease virus (Freeman, et al., Mol. Ther., 13:221-228 (2006), or VSV (Stojdl, et al., Cancer Cell., 4:263-275 (2003)). VSV infections do not integrate (and in fact do not even enter the nucleus), and in animals, including humans, are eliminated from the body within 1-2 weeks by the systemic immune system. In regions of Central America where VSV is endemic, local human populations are seropositive for VSV, with no obvious link to substantive disease (Tesh, et al, 1969). VSV is rare in the US, indicating a very low level of pre-existing immunity. VSV has been approved for human clinical trials where VSV is used as a vaccine vector to immunize people against dangerous viral or bacterial pathogens (Roberts et al, 1999; Rose et al, 2000; Schwartz et al, 2010).
Another type of attenuated VSV, VSV-M51, shows a reduced ability to block nuclear pores, thereby allowing normal cells to up-regulate antiviral defenses, and has been described as showing an enhanced safety profile (Stojdl, et al., Nat. Med., 6:821-825 (2000); Stojdl, et al., Cancer Cell, 4:263-275 (2003)). However, this attenuated virus can still generate lethal outcomes after CNS injection.
Some oncolytic viruses have been tested in early phase 1 clinical trials, but although the viruses were found to be safe, little therapeutic effect was seen, and then only in a subset of patients (Zemp, et al., Cytokine Growth Factor Rev., 21:103-117 (2010)), underlining the importance of continuing efforts to find more effective oncolytic viruses and delivery strategies (Liu, et al., Mol. Ther., 16:1006-1008 (2008)). Accordingly, despite the advances in the development and use of oncolytic viruses for treatment of cancer, there remains a need for improved virus and methods of use therefore for safely and effective treating cancers such as glioblastoma.
Therefore, it is an object of the invention to provide recombinant oncolytic viruses with improved safety and efficacy profiles.
It is a further object of the invention to provide pharmaceutical compositions including an effective amount of recombinant oncolytic viruses to treat cancer in a human subject.
It is another object of the invention to provide methods of using recombinant oncolytic virus to kill cancer cells.
It is a further object of the invention to increase the body's immune response against cancer cells.
It is a further object to generate a safer virus-based vaccine against other non-related microbial antigens.